This invention relates generally to the asymmetric synthesis of quinazolin-2-ones that are useful as inhibitors of HIV reverse transcriptase.
Non-nucleoside reverse transcriptase inhibitors (NNRTI""s) like those of Formulas Ia and Ib shown below: 
are currently being clinically investigated. As a result, large quantities of these compounds are needed to satisfy clinical demands.
Tucker et al (J. Med. Chem. 1994, 37, 2437-2444) describe the preparation of 4-(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2(1H)-ones (i.e., NNRTI""s) by the addition of aryl acetylides to N-protected quinazolinone precursors. A typical example is shown below. 
Unfortunately, the addition of the aryl acetylide requires the quinazolinone precursor to be N-protected. An undesirable deprotection step is consequently required after acetylide addition. Other papers have described similar N-protected routes (see J. Org. Chem. 1995, 60, 1590-1594; Tetr. Lett. 1994, 35(37), 6811-6814).
It can be seen that preparation of NNRTI""s is difficult. Thus, it is desirable to find efficient syntheses of NNRTI""S, specifically those of Formulas Ia and Ib.
Accordingly, one object of the present invention is to provide novel asymmetric processes for preparing quinoxazin-2-ones.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formulas Ia and Ib can be prepared from quinazolinone precursors of Formulas IIa and IIb: 
via chiral moderated asymmetric addition of cyclopropylacetylene.
In an embodiment, the present invention provides a novel process for making a compound of Formula Ia or Formula Ib: 
comprising: contacting a quinazolinone precursor of Formula IIa or IIb: 
with cyclopropylacetylide in the presence of a chiral moderator and a base, wherein the chiral moderator is a compound selected from: 
In another preferred embodiment, the chiral moderatoris a compound selected from: 
In another preferred embodiment, the chiral moderator is a compound selected from:
In another preferred embodiment, the chiral moderator (CM) is selected from: 
In another preferred embodiment, the chiral moderator is CM1.
In another preferred embodiment, the chiral moderator is CM2.
In another preferred embodiment, the chiral moderator is CM3.
In another preferred embodiment, cyclopropylacetylide is lithium cyclopropylacetylide (Li-CPA).
In another preferred embodiment, contacting is performed with tetrahydrofuran as a solvent.
In another preferred embodiment, the base is selected from lithium hexamethyldisilazide, n-BuLi, s-BuLi, t-BuLi, and n-HexLi.
In another preferred embodiment, the base is n-HexLi or n-BuLi.
In another preferred embodiment, the base is lithium hexamethyldisilazide (Li-HMDS).
In another preferred embodiment, contacting is performed with tetrahydrofuran as a solvent and lithium hexamethyldisilazide as a base.
In another preferred embodiment, contacting is performed by adding a solution, comprising: a quinazolinone precursor to a solution comprising chiral moderator, Li-CPA, and base.
In a more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: Li-CPA, chiral moderator and base to a solution comprising quinazolinone precursor.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: Li-CPA and base to a solution comprising chiral moderator and quinazolinone precursor.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: chiral moderator and quinazolinone precursor to a solution comprising Li-CPA and base.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: Li-CPA to a solution comprising quinazolinone precursor IIa or IIb, chiral moderator, and base. Preferably LiHMDS is used as base for this route.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to 4 to 4.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution comprising quinazolinone precursor IIa or IIb, chiral moderator, and base to a solution, comprising: Li-CPA.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to 4 to 4.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: deprotonated chiral modifier to a solution, comprising: quinazolinone precursor and LiHMDS and then adding a solution, comprising: Li-CPA.
In another more preferred embodiment, the stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to about 1 equivalent of LiHMDS to 3 to 3.6 equivalents of n-BuLi to 1 equivalent of quinazolinone precursor.
In another preferred embodiment, contacting is performed by adding a solution, comprising: quinazolinone precursor to a solution, comprising: a chiral modifier, cyclopropylacetylene, and LiHMDS and then adding a solution, comprising: Li-CPA.
In another more preferred embodiment, the stoichiometric ratios are about 3 equivalents of chiral moderator to about 1 equivalent of cyclopropylacetylene to 1 to 1.5 equivalents of Li-CPA to about 4 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
In another embodiment, the quinazolinone precursor of Formula IIa or IIb: 
is prepared by the process, comprising: dehydrating a compound of Formula IIIa or IIIb: 
In another preferred embodiment, dehydrating is performed by heating a compound of Formula IIIa or IIIb in a solvent selected from toluene and xylenes and mesitylenes in the presence of a water scavenger.
In another preferred embodiment, dehydrating solvent is xylenes, the water scavenger is a Dean-Stark trap, and the reaction is conducted in the presence of benzene sulfonic acid.
In another embodiment, dehydrating solvent is mesitylene, with or without the water scavenger as a Dean-Stark trap.
In another preferred embodiment, the reaction solution resulting from dehydration is reduced in volume and used in the contacting reaction without further purification.
In another embodiment, the present invention provides a novel process for making a compound of Formula Ia or Formula Ib: 
comprising: contacting a quinazolinone precursor of Formula IIa or IIb: 
with cyclopropylacetylene in the presence of a chiral moderator and a base, wherein the chiral moderator is a compound that provides an enantiomeric excess of at least 30 to 100%.
In a preferred embodiment, the chiral moderator is a compound that provides an enantiomeric excess of at least 60 to 99%.
In another preferred embodiment, the chiral moderator is a compound that provides an enantiomeric excess of at least 80 to 99%.
In another preferred embodiment, the chiral moderator is a compound that provides an enantiomeric excess of at least 85 to 99%.
In another embodiment, the contacting is performed in the presence of an additive.
In another embodiment, the additive is selected from benzene sulfonic acid, lithium trifluoromethanesulfonate (lithium triflate), lithium benzenesulfonate, 2,2,2-trifluoroethanol, (+)-camphorsulfonic acid, pyridinium p-toluenesulfonate (PPTSA), and methanesulfonic acid.
In another embodiment, the additive is benzene sulfonic acid.
In another embodiment, the stoichiometric ratios are in the range of about 0.05 to 1 equivalents of benzene sulfonic acid to 1 equivalent of quinazolinone.
In another embodiment, the stoichiometric ratios are about 0.15 equivalents of benzene sulfonic acid to 1 equivalent of quinazolinone.
In another embodiment, dehydrating is performed by heating a compound of Formula IIIa or IIIb in mesitylenes.
In another embodiment, dehydrating is performed by heating a compound of Formula IIIa or IIIb in mesitylenes in the presence of a water scavenger.
As used herein, the following terms and expressions have the indicated meanings. It will be appreciated that the compounds of the present invention contain an asymmetrically substituted carbon atom, and may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
The processes of the present invention are contemplated to be practiced on at least a multigram scale, kilogram scale, multikilogram scale, or industrial scale. Multigram scale, as used herein, is preferably the scale wherein at least one starting material is present in 10 grams or more, more preferably at least 50 grams or more, even more preferably at least 100 grams or more. Multikilogram scale, as used herein, is intended to mean the scale wherein more than one kilogram of at least one starting material is used. Industrial scale as used herein is intended to mean a scale which is other than a laboratory scale and which is sufficient to supply product sufficient for either clinical tests or distribution to consumers.
Suitable ether solvents include, but are not intended to be limited to, dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, or t-butyl methyl ether.
Suitable hydrocarbon solvents include, but are not intended to be limited to, benzene, cyclohexane, pentane, hexane, hexanes, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene, m-, o-, or p-xylene, mesitylene, octane, indane, nonane, or naphthalene.
Chiral moderator, as used herein, is intended to represent a compound with one or more chiral centers, preferably two chiral centers. The chiral moderator being capable of increasing the enantiomeric excess of the desired enantiomer compared with the addition reaction run without the presence of a chiral moderator.
Base, as used herein, is intended to represent a basic compound capable of deprotonating cyclopropylacetylene. Examples of such bases included, but are not intended to be limited to, n-BuLi, s-BuLi, t-BuLi, and n-HexLi, and LiHMDS.
Contacting, as used herein, is intended to represent bringing the reactants together in an appropriate medium such to allow the chemical reaction to take place.
Additives are compounds which increase the enantiomeric excess of the reaction. The additives are acids comprised of a non nucleophilic or non reactive conjugate base. Examples of such additives include, but are not intended to be limited to, benzene sulfonic acid, lithium benzenesulfonate, lithium trifluoromethanesulfonate (lithium triflate), 2,2,2-trifluoroethanol, (+)-camphorsulfonic acid, pyridinium p-toluenesulfonate (PPTSA), and methanesulfonic acid. As used herein, cyclopropylacetylene is intended to represent the use of cyclopropylacetylene in the reaction mixture. Typically, the cyclopropylacetylene is deprotonated in situ. Alternatively, cyclopropylacetylene represents the use of cyclopropylacetylide, which may be in the form of lithium cyclopropylacetylide, in the reaction mixture. The cyclopropylacetylide would be prepared prior to its addition to the reaction mixture.
The processes of the present invention can be practiced in a number of ways depending on the solvent, base, chiral moderator, and temperature chosen. As one of ordinary skill in the art of organic synthesis recognizes, the time for reaction to run to completion as well as yield and enantiomeric excess will be dependent upon all of the variables selected.
The following scheme shows a representation of the overall sequence of the present invention. While a specific chiral moderator is shown, this scheme is intended to be representative of the overall synthesis of compounds of Formulas Ia and Ib. 
Dehydration
The quinazolinone precursor (IIa or IIb) can be prepared by known methodologies. For example, 3,4-difluoro-2-trifluoroacetyl-aniline can be reacted with potassium cyanate to yield to above precursor (IIa). The desired 6-chloro precursor can be prepared from 4-chloro-2-trifluoroacetyl-aniline.
Dehydration can be effected via a number of ways known to those of skill in the art. For example, the hydroxy group can be modified and cleaved (e.g., using acetic anhydride and a base). Another method is heating a compound of Formula IIIa or IIIb in a solvent selected from toluene and xylenes and mesitylene with or without the presence of a water scavenger. Alternatively, the dehydrating solvent is xylenes and the water scavenger is a Dean-Stark trap or a corresponding equivalent. Alternatively, the dehydrating solvent is mesitylenes with or without a water separator such as a Dean-Stark trap or a corresponding equivalent. Alternatively, the reaction is conducted in the presence of a catalyst (e.g., benzene sulfonic acid). Alternatively, o-xylene is used as the dehydration solvent. Alternatively, benzene sulfonic acid is used as the catalyst and is greater than 90% pure. Alternatively, the benzene sulfonic acid is 97% pure. In another method, the dehydrating solvent is mesitylene.
After dehydration, the resulting solution can be used directly (i.e., without purification) in the contacting step. Preferably, the solution resulting from the dehydration is reduced in volume by removal of a portion of the dehydration solvent prior to use in the contacting step.
Contacting
Enantiomeric excess (ee) is calculated by subtracting the yield of the undesired isomer from the yield of the desired isomer. For example, if the compound of Formula Ia is formed in 70% yield and its corresponding enantiomer in 30% yield, then the ee would be 40%.
A compound of Formula IIa or IIb is contacted with a chiral moderator in the presence of cyclopropylacetylene (CPA) and a base to form a compound of Formula Ia or Ib. Preferably, the chiral moderator is a compound that provides an enantiomeric excess of at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 95, to 100%, preferably an enantiomeric excess of at least 60, 65, 70, 75, 80, 85, 90, 95, to 99%, more preferably an enantiomeric excess of at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, to 99%, and even more preferably an enantiomeric excess of at least 85, 86, 87, 88, 90, 91, 92, 93, 94, 95, 96, 97, 98, to 99%. The reaction temperature is preferably from xe2x88x9220 to reflux of the solution, more preferably from xe2x88x9220 to room temperature. The yield of the compound of Formula Ia or Ib is preferably in excess of 50, 55, 60, 65, 70, 75, 80, 85, to 90%, more preferably in excess of 70, 75, 80, 85, to 90%.
CPA can be prepared by a number of routes known in the art. In one aspect of the invention, CPA is used as its corresponding acetylide (e.g., Li-CPA). In other words, CPA is deprotonated with a base prior to use in the contacting reaction. In this instance, a preferred acetylide is Li-CPA. Bases that can be used to deprotonate CPA include Li-HMDS (lithium hexamethyldisilazide), n-BuLi, s-BuLi, t-BuLi, and n-HexLi. In another aspect of the invention, CPA is added directly into the contacting reaction and is deprotonated in situ.
Bases that can be used for the present contacting reaction include n-BuLi, s-BuLi, t-BuLi, n-HexLi, and lithium hexamethyldisilazide (LiHMDS). The chosen base will depend upon the order in which the materials are contacted. A preferred base for the contacting reaction is LiHMDS. Another preferred base for the contacting reaction is n-HexLi. A third preferred base for the contacting reaction is n-BuLi. In another aspect of the invention, LiHMDS is prepared in situ by the addition of another lithium base to the contacting reaction having HMDS (hexamethyldisilazane) therein. The base used in the contacting reaction can serve a number of purposes. One purpose for the base is the deprotonation of the quinazolinone precursor. It should be noted that alkyl lithium bases will generally react with the quinazolinone precursors. Thus, when an alkyl lithium base is used, it should be used in a solution comprising other than the quinazolinone precursor.
The chiral moderator chosen can be one known to one of skill in the art. Chiral moderators that have been found useful (i.e., an ee of greater than 30%) include the moderators described in the embodiments. In some instances, it will be necessary for the chiral moderator to be deprotonated prior to its addition to another reactant. Alkyl lithium bases are useful for the deprotonation. Preferably n-BuLi or LiHMDS is used to deprotonate the chiral moderator. The chiral moderator can be recycled in the present reaction. For example, after contacting is complete, the chiral moderator is preferably isolated and used in another contacting reaction.
As one of ordinary skill in the art would recognize, a wide variety of stoichiometries can be selected. The stoichiometric ratios chosen will depend upon the route of addition. In general, for each equivalent of quinazolinone precursor there should be about 3 equivalents of chiral modifier, 4 equivalents of base (or bases) and at least one equivalent of cyclopropylacetylene, whether used as is or as a cyclopropylacetylide (generally at least 1.5 equivalents are used). Preferably, the stoichiometric ratios are chiral moderator 2 to 6 equivalents, cyclopropylacetylene 1 to 5 equivalents, base 4 to 8 equivalents, to quinazolinone precursor 1 equivalent. More preferably, the stoichiometric ratios are chiral moderator 3 to 4 equivalents, cyclopropylacetylene or acetylide 1 to 4 equivalents, base 4 to 7 equivalents, to quinazolinone precursor 1 equivalent. When the chiral moderator is CM2, the cyclopropylacetylide is Li-CPA, the base is LiHMDS, and quinazolinone precursor is IIa, then the preferred stoichiometric ratios are 3.6:3.0:6.6:1. Alternatively, when the chiral moderator is CM2, cyclopropylacetylene is used, the base is n-BuLi, HMDS is used, and the quinazolinone precursor is IIb, then the stoichiometric ratios are 3.6:1.5:6.1:1.
A variety of ways of contacting are contemplated by the present invention. A first way of contacting is by adding a quinazolinone precursor solution to a solution comprising chiral moderator, Li-CPA, and base. Preferably LiHMDS or HexLi is used as base for this route. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 2.5 to 3.5 equivalents of cyclopropylacetylide to 5 to 7 equivalents of base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A second way of contacting is by adding a Li-CPA, chiral moderator and base solution to a solution comprising quinazolinone precursor. Preferably LiHMDS or HexLi is used as base for this route. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 2.5 to 3.5 equivalents of cyclopropylacetylide to 5 to 7 equivalents of base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A third way of contacting is by adding a Li-CPA and base solution to a solution comprising chiral moderator and quinazolinone precursor. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 2.5 to 3.5 equivalents of cyclopropylacetylide to 5 to 7 equivalents of base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A fourth way of contacting is by adding a chiral moderator and quinazolinone precursor mixture to a solution comprising Li-CPA and base. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 2.5 to 3.5 equivalents of cyclopropylacetylide to 5 to 7 equivalents of base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to about 3 equivalents of Li-CPA to about 6.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A fifth way of contacting is by adding a Li-CPA solution to a solution comprising quinazolinone precursor IIa or IIb, chiral moderator, and base. Preferably LiHMDS is used as base for this route. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 1 to 2.5 equivalents of cyclopropylacetylide to 3.5 to 5.5 equivalents of base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to 4 to 4.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A sixth way of contacting is by adding a solution comprising quinazolinone precursor IIa or IIb, chiral moderator, and base to a Li-CPA solution. Preferably LiHMDS is used as base for this route. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 1 to 2.5 equivalents of cyclopropylacetylide to 3.5 to 5.5 equivalents of base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to 4 to 4.6 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A seventh way of contacting is adding a deprotonated chiral modifier to a solution comprising quinazolinone precursor and LiHMDS and then adding a solution comprising Li-CPA. The chiral modifier is preferably deprotonated with a second base, e.g., n-BuLi. With this method of addition, the preferred stoichiometric ratios are 2.5 to 4.5 equivalents of chiral moderator to 1 to 2.5 equivalents of cyclopropylacetylide to 1 to 1.5 equivalents of LiHMDS to 2.5 to 4.5 equivalents of second base to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are 3 to 3.6 equivalents of chiral moderator to 1 to 1.5 equivalents of Li-CPA to about 1 equivalent of LiHMDS to 3 to 3.6 equivalents of n-BuLi to 1 equivalent of quinazolinone precursor.
An eighth way of contacting is by adding a quinazolinone precursor solution to a solution comprising a chiral modifier, cyclopropylacetylene, and LiHMDS and then adding a solution comprising Li-CPA. With this method of addition, the preferred stoichiometric ratios are 2.5 to 3.5 equivalents of chiral moderator to 1 to 1.5 equivalents of cyclopropylacetylene to 1 to 2.5 equivalents of Li-CPA to 3 to 5 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor. The more preferred stoichiometric ratios are about 3 equivalents of chiral moderator to about 1 equivalent of cyclopropylacetylene to 1 to 1.5 equivalents of Li-CPA to about 4 equivalents of LiHMDS to 1 equivalent of quinazolinone precursor.
A ninth way of contacting is by adding a quinazolinone precursor solution to a solution containing the chiral moderator, HMDS, and n-BuLi. A cyclopropylacetylene solution is added to the reaction. With this method of addition, the preferred stiochiometric ratios are 3.6 equivalents of chiral moderator to 1.5 equivalents of cyclopropylacetylene, to 3.0 equivalents of HMDS, to 6.1 equivalents of n-BuLi, to 1 equivalent of quinazolinone presursor.
A tenth way of contacting is by adding a solution of n-butyl lithium to a solution containing the chiral moderator, HMDS, and an additive such as benzene sulfonic acid. The quinazolinone is added to the reaction followed by a cyclopropylacetylene solution. With this method of addition, the preferred stiochiometric ratios are 3.6 equivalents of chiral moderator to 1.2 equivalents of cyclopropylacetylene, to 3.0 equivalents of HMDS, to 6.1 equivalents of n-BuLi, to 1 equivalent of quinazolinone presursor.
An eleventh way of contacting is by adding to a solution chiral moderator, HMDS, a solution of n-butyl lithium, followed by the quinazolinone, benzene sulfonic acid, and then cyclopropylacetylene. With this method of addition, the preferred stiochiometric ratios are 3.6 equivalents of chiral moderator to 1.2 equivalents of cyclopropylacetylene, to 3.0 equivalents of HMDS, to 6.1 equivalents of n-BuLi, 0.15 equivalents of benzene sulfonic acid, to 1 equivalent of quinazolinone precursor.
In general, the benzene sulfonic acid is present in the range of about 0.05 to 1 equivalents to 1 equivalent of quinazolinone precursor. Alternatively, the benzene sulfonic acid is present in about 0.15 equivalents to 1 equivalent of quinazolinone precursor.
Preferably, the reaction is performed with tetrahydrofuran as a solvent. A cosolvent may also be present. The cosolvent is preferably selected from an ether or hydrocarbon. More preferably the cosolvent is selected from diethyl ether or hexanes. A quinazolinone solution can comprise quinazolinone and a solvent selected from toluene, xylenes, o-xylene, ethylbenzene, mesitylene and mixtures thereof. Preferably, a quinazolinone solution comprises quinazolinone and o-xylene, mesitylene or toluene. Alternatively, a quinazolinone solution comprises quinazolinone and o-xylene. Alternatively, a quinazolinone solution comprises quinazolinone and mestiylenes. A Li-CPA solution can comprise Li-CPA and a solvent selected from THF, methylcyclohexane (MCH), and hexanes. Preferably, a Li-CPA solution comprises Li-CPA and THF. A cyclopropylacetylene solution can comprise cyclopropylacetylene and toluene. A chiral moderator solution can comprise a chiral moderator and a solvent selected from THF, toluene, and mixtures thereof.
The following scheme describes the synthesis of 4xcex2-morpholinocaran-3xcex1-ol, CM2. 
Step a
3-Carene is oxidized to its corresponding epoxide using m-CPBA in dichloromethane at room temperature in 6-8 hours.
Step b
The epoxide is opened with ammonium hydroxide, 350 psig, at 150xc2x0 C. in about 24 hours.
Step c
The amino group is converted to a morpholino group by refluxing in toluene in the presence of bromoethyl ether and sodium bicarbonate to give the final product in about 20 hours.
Alternative Steps b and c
Morpholine can be used to ring open the epoxide and directly provide 4xcex2-morpholinocaran-3xcex1-ol. This can be done by adding morpholino to the epoxide in the presence of lithium perchlorate (see J. Org. Chem. 1998, 20, 7078-7082), magnesium chloride, magnesium bromide, or lithium halides.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments that are given for illustration of the invention and are not intended to be limiting thereof.